Hydroxyguanidine O-carbamates

ABSTRACT

Disclosed herein are particular variously substituted 2hydroxyguanidine O-carbamates, useful as antihypertensive agents, made by reacting an hydroxyguanidine with an isocyanate. Exemplary is 1-methyl-1-n-propylhydroxyguanidine O-(N-methyl carbamate).

United States Patent Cherkofsky Feb. 18, 1975 l l HYDROXYGUANIDINE O-CARBAMATES [58] Field of Search..... 260/564 A, 564 G, 556 AR, [75] Inventor: Saul Carl Cherkofsky, wilr nington, 260/556 B1556 S1 559 R1559 T1559 A1558 Delv D, 557, 565

[73] Assignee: E. I. du Pont deNemours and [56-] References Cited Company, W1lm1ngt0n, Del. I 1 73 UNITED STATES PATENTS [22] June 3.21m37 11/1965 Payne et al 260/566 AC [21] App]. No.: 373,147 1742056 6/1973 Henderson 260/564 G Apphcamm 9 Primary ExaminerLe0n Zitver conlmuanon'm'pan of AssistantExam1'r1erGerald A. Schwartz 1972, abandoned.

[52] U.S. CL... 260/564 G, 260/239 B, 260/239 BF, ABSTRACT 260/556 B, 260/556 S, 260/558 R, 260/558 D, 260/559 R, 260/564 E, 260/565, 260/566 R, 424/244, 424/267, 424/274, 424/321, 424/324, 424/326 Int. Cl C07c 129/08 Disclosed herein are particular variously substituted Z-hydroxyguanidine O-carbamates, useful as antihypertensive agents, made by reacting an hydroxyguanidine with an isocyanate. Exemplary is l-methyl-l-npropylhydroxyguanidine O-(N-methyl carbamate).

12 Claims, N0 Drawings 1 2 HYDROXYGUANIDINE O-CARBAMATES o II CROSS-REFERENCE TO RELATED APPLICATION l l This application is a continuation-in-part of my con 3 pending application Ser. No. 283,775, filed Aug. 25, mm 1972 now abandoned. Rg/

BACKGROUND OF THE INVENTION 1. Field of the Invention wherein R, R and R are selected from the group con- This invention concerns variously substituted 2- l0 sisting of(A) hydrogen, (B) an aliphatic hydrocarbon hydroxyguanidine O-carbamates. group of 1-8 carbon atoms containing up to two sub- 2. Description of the Prior Art stituents selected from the group consisting of F, Cl, Br

J. V. Braun and R. Schwarz, Ber., 36, 3660 (1903) and alkoxy of 14 carbon atoms and (C) a group of the describe the preparation of the hydroxyguanidines: formula where R (1); R CH R R n-propyl; and R, wherein R 1). X is F, Cl, C C} alkyl, C -C alkoxy, N0 CF C. Belzecki et al., J. Chem. Soc., Chem. Comm. 806, R"R"NC(), R"'RNSO or RSO- (I970). Reaction of hydroxylamine with 1,1- m 0-2; disubstituted cyanamides yields l,l-disubstituted-2- n 0-3; hydroxyguanidines (I) y or N,N-disubstituted-l- R and R are H or C -C alkyl;

aminohydroxyformamidine (II); R is CF or C -C alkyl; with the proviso that R and I R together can be (CH where y is 4-9; and

R is hydrogen or C -C alkyl; with the further provi KI RH sos that f'fi g -C=HH I. up to one of R, R and R is selected from (A), up R R/ to two of R, R and R is selected from (B), and

Non g u to one of R, R and R is selected from (C);

P 2. when R is methyl and R is hydrogen, R is not un- (I) substituted phenyl or unsubstituted benzyl;

3. when R is methyl and R is hydrogen, R is not unsubstituted phenyl; and

depending on the solvent and the cyanamide substitu- 4. when one of R, R and R is hydrogen and the ents. Various acyl derivatives but no carbamates are other two R groups are selected from (B), the total disclosed. 40 carbon atoms in the said other two groups is 3-9. C. Belzecki et al., Tetrahedron Letters, No. 22, I879 The compounds have a carbon double bond nitrogen (I970). l,3-Ethylene-2-hydroxyguanidine and 1,3- arrangement which allows the existence of syn/anti isotrimethylene-2-hydroxyguanidine are unstable but can mers and these are intended to be included within the be prepared in excess acetic acid or by use of the HCl scope of the invention.

salt of one reactant. The invention also embraces an antihypertensive Acetylation yielded O- and N-acetyl derivatives and composition comprising one or more compounds havacylation with ethyl chloroformate yielded the 0- ing the general formula above and a physiologically ethoxycarbonyl product. No earbamates are disclosed. inert pharmaceutical carrier.

U.S. Pat. No. 3,505,336 discloses hydroxyguanidines of the type Process The process for preparing the compounds of the in- R vention involves the reaction or a hydroxyguanidine R OH 1 with an isocyanate at a temperature in the range of 20 to 50C. The reaction may be represented as: H c R NR2 v i 0 II 1 H n-o-c-mm n 3 l 3 and their diacctyl derivatives as antihypertensive 6O R N00 -cagents. R

DESCRIPTION OF THE INVENTION where R, R R and R are as defined above.

The invention IS an antihypertensive compound of When R 15 hydrogen, an alternative process reacts the general formula I the hydroxyguanidine is salt form,

3 150K 'HX N-C-NHRB 12 with an alkali metal cyanate, MOCN, wherein X is F. C1 or Br. and M is Na, K or Li.

The reactions for making hydroxyguanidine O- carbamates wherein R is hydrogen are conducted in water solution. In such cases, cyanic acid is reacted with the hydroxyguanidine. Where the hydroxyguanidine salt is reacted with the alkali metal cyanate, the cyanic acid is formed in situ.

The hydroxyguanidine (l-carbamates of the invention wherein R is a C C; aliphatic hydrocarbon group are prepared by adding the corresponding isocyanate to a solution of the hydroxyguanidine in a nonhydroxylic organic solvent preferably dioxane, tetrahydrofuran, ethyl acetate, chloroform, methylene chloride, diethyl ether, benzene, or the like, at a rate to maintain the.

temperature in the range of about 20." to +50"C.

DETAILS OF THE INVENTION The 1,1-disubstituted Z-hydroxyguanidine precursors are made from the corresponding cyanamides and hydroxylamine according to the reaction:

The procedure of J. V. Braun and R. Schwarz, Ber., 36, 3660 (1903) may be used or the general procedure illustrated hereafter where the cyanamide is methyl-nbutyl cyanamide. I An example of Brauns procedure comprises adding 1 mole equivalent of methylphenylcyanamide to a methanol solution of slightly more than 1 mole equivalent of free hydroxylamine. Reaction starts immediately at room temperature with heat evolution and yellowing. After some time the mixture is evaporated and an oil-crystalline mixture is separated into unreacted methylphenylcyanamide (ether-soluble. waterinsoluble) and the sought l-methyl-l-phenylhydroxyguanidine (soluble hot water and alcohol). Final purification is effected by crystallization from al cohol or hot water to give pure mcthylpheny[hydroxyguanidine. melting at 102C.

General Procedure A 500-ml, 3-necked flask, fitted with a reflux condenser, magnetic stirrer and addition funnel was charged with 11.2 g (0.1 mole) of methyl-nbutylcyanamide, about 100 ml of ethanol and 13.9 (0.2 mole) of hydroxylamine hydrochloride. A solution of 10.6 g (0.1 mole) of sodium carbonate and ml of water was added dropwise within a few minutes, the mixture refluxed for 2 hours and then cooled. The mixture was diluted with 200 ml of water and extracted four times with 100 ml of methylene chloride. The combined methylene chloride layers were dried and concentrated in a rotary evaporator. The residue from evaporation of the methylene chloride was purified by methanol elution from silica gel (silicAR CC-7, Mallinckrodt, special for chromatography) and identified as l-methyl-1-n-butylhydroxyguanidine by its nmr spectrum; (CDCI 6 0.9 (t, 3); 1.4 (m, 4); 2.7 (s. 3); 3.1 (t. 2); 6.1 (b, 3).

' Employing the general procedure set out above. the l,l-disubstituted hydroxyguanidines of Table 2 are made by reacting the corresponding cyanamides of Table l with hydroxylamine. The cyanamides of Table 1 are known or their synthesis will be obvious to those skilled in the art, especially in view of the references cited.

TABLE 1 cyanamides R1R2NCN BOP. .e 32222222 n-c a 87/12 Ainley 5 9 J. Chem. soc.

98 9 19) n-C H 74/12 i-Ct ll 81/12.

sec-(MR 81/12 n-C H 52/O.45 gglstein, g, I, n- 0 1113 /0 l- I 02H 69/12 Beilstein, g, 121 n-c n 81/12 n-C H 5l/O.5 Beilstein, t 144 n-ci;a 78/o.5 lggjlstein, 5, II,

(2 H -ca 5/o.2 Beilslzein, .12, II,

TABLE 2 continued Used to make 1 2 examole ,R l mg mar 15 methyl ieopropyl 011 g d; 6);)2.6 (a, 3); 3-95 v .a 16 CH3 arch-H9 9%: :9 l l 3) 1 -1l0' 5 1.6 m, 8); 2.8 (a, 3); 3-3 (m, 1); 17 methyl 321 5133 05 2.; 81 1); 7.9 (broad, 2); 10.6

3 c.11 1 011;,1 oil 5 1 3 3-3-3-5 Mtwl M50503? on 4.5 ?tf 1); 5.6 (in-om, 3)

l .8' (Gl m-1 008 0359 011 16 5;: g), 3.5 (m 12), 6 21 methyl 2-chlorobenzy1 99-100 ;)2.; az 3); 3.) (a, 2); 6 (brold v ,8 ,3; ).2(,s, 2); 22 methyl 2 mqthombenzyl 71 72 2-2 '(fbgadln? m uzgaq, 3 methyl g-methylbenzyl 103-1035 2 2.?b(s;d3);)2.; 91289 6 425 (5, 2);

2 methyl 7 n-nitrobenzyl 159-160 giug fl i 5 3):

- 2 2 a I 2 c 1 3 t-dihl 119-120 '0 2.7 (s, 3); L25

5 m w enzyi m 3); 7.0-7.5 (m, 3)

methyl -chlorobenzyl 102-3 ;)2.;52(:,u3z; (8| 2); (broad! 27 ethyl benzyl 83.5-84.5 glzirgza 22%; 4.3 (s, 2);

r I J I 28 I 1 benz 1 69-70 0 0,8 (t, 3)- 1.5 (m 2)- 3.1 (t, 2);

- m B, 2); $4 5); 7.3 (s. 5)

29 methyl B-phenethyl 934 3 $.'(!m( 5)3;)2.;52(?; 3.3 (t, 2);

I I V I l I 30 methyl n-rluorobenzyl 101-2 E g.'(Ib6ag);3l-.265 ga g)( O 31 PM tritium;2242,2- 32 Irpm/W1 phenyl lO l-j 2 g.% g ?)):t.g mzmf))3,5 (t, 2);

r 33 CH n-C 60.9 t 3;1. r m +;2;7

3 a 5.30 ,3) 3h on 0 -cu 89-90 6 2.65 (e 3 4.2 (a 2); 6.5

(1) Ber. 3 3660 (1903). H (2) Beliecki et 01. J. Chem. $0 Chem. comm. 806, (1970).

e l,3-diSUbSIiIut6d 2- y dr0xyguenidin pre rsor low mercuric oxide and 10 g of anhydrous sodium sulare prepared by the following r actl n qu nce n fate. The mixture is stirred vigorously for 2 hours, then general Procedure: is filtered. The filtrate is a solution of the crude l,3

I HOB 1 NH 03 L R m1cmm To a slurry of 0.1 mole or the1,3-disubstituted thiodisubstituted carbodiimide. (Alternatively, some carurea in ml ether is added 86.5 g (0.4 mole) of yelbodiimides can be purchased commercially.)

To the solution of the carbodiimide in ether is added shown in German patent application No. 2.040628 at a solution of hydroxylamine in methanol prepalaid open for publication on Feb. 24, 1972, to M. Gross pred from 6.95 g (0.] mole) of hydroxylamine hydrot al, as follows. chloride and 5.6 g (0.1 mole) of potassium hydroxide in 60 ml methanol (filtered to remove potassium chloride). The reaction mixture of the carbodiimide and hydroxylamine is stirred at room temperature one-half hour, then rotary evaporated. The residue is dissolved A solution of 4.1 g (0.05 mol) hydroxylamine hydrochloride in 30 ml dry methanol was cooled to 0 to 5. A methanolic solution of 4.2 g (0.075 mol) of potassium hydroxide was added dropwise. The mixture was i 100 l water containing enough concentrated stirred for 30 minutes while adding a solution of 4.0 g drochloric acid to make the solution acidic. Extraction of 'P Y 'N' y with methylene chloride removes neutral impurities. in ml of dry methanol. The mixture was stirred for The aqueous acidic solution is then treated with sodium 3 hours and finally warmed to room temperature. The hydroxide until basic, then extracted again with methbulk of the solvent was distilled, the residue poured yhihc Chloridc- The methylene Chloride tracts are into water and the precipitated product collected on a dried and rotary evaporated to give the Crude l,3- filter. After drying, the product was crystallized from dlsubsmhted hydroxyguanidlhe, which can generally benzene/benzine (l/l yield 0.8 g (18 percent of the be recrystallized from mixtures of methylene chloride theoretical); mp 1340433650. and hexane.

The properties of representative 1,3-disubstituted hydroxyguanidines prepared by the above procedure are listed in Table 3.

20 SPECIFIC EMBODIMENTS OF THE INVENTION The l,l,3-trisubstituted hydroxyguanidine precur- The following are illustrative examples in which all sors are prepared by the reactions: parts are by weight unless otherwise stated.

As an example, l,l-dimethyl-3-phenyl-2- EXAMPLE 1 hydroxyguanidine 1= z h l-Methyl-l-n-butylhydroxyguanidine O-(N-Methyl melted at l34-l36; nmr, a 2.65 (s, 6); 7.1 (m, 5); 7.8 Carbamate) (broad, 2). A 100-ml, 3-necked flask, fitted with a magnetic stir- This compound was prepared by the procedure 40 rer, reflux condenser and addition funnel was charged TABLE IOH fl 1,3-Dieubet1tuted Hydrownidinee R -NH-C-1IHR an R1 R3 59 rear Anelveie (Avere e 35 :leoieo- 12h-8 5 1.15 (d, 12); Ref: G. Zinner end 8. Gross,

1 m a r. 395 1709 (1972) nropyl pr p! 2 3) L t 1 1 o- S t-6 6 0. e 6 3 Ce1cd:0 5.6 ;r-r, 10. i1;

36 m h, bt ltyl I: g I: am

e I 2.; a: 2 i round: 0; #358; a, 10.11; 5-6 broed, 3) N, 2 .50.

Reectien o! tneee respective eonpounde with methyl ieecyenete yielded:

35 1,3-d11eoprepy1 hyeroxnuenidine O-(I-eettwl eerbemete) 36 l-mehhyt-a-teobuliyl. hydrexy uenldtne O-(N-nethyl oerbemete) spectrum.

Anal. C H N Calcd for C,.H N,O 47.51; 8.97; 27.70

Found: 48.0]; 8.85. 27.12

nmr (CDCl 5 0.95. 1.4 (t, m, 7); 2.8 (s, 3); 2.85 (d, 2

3); 0 3.15 (t, 2); 4.8 (b, 2); 6.5 (b, l).

EXAMPLE 2 l-Methyl-l -n-propylhydroxyguanidine 0-( N-Methyl carbamate) This compound was prepared by a procedure analogous to that of Example 1, and was identified by proximate analysis and nmr spectrum.

Anal. I C H N Calcd for C,H|BN4O,: 44.67; 8.57, 29.76 Found: 43.46; 8.53: 29.l8

nmr (CDCl,,): 8 0.9 (t, 3); 1.5 (sex. 2); 2.8 (s, 3);

2.85 (d, 3); 3.1 (r, 2); 4.9 (b, 2 6.6 (,b, l).

EXAMPLES 3-32 The following compounds were prepared by a proce dure similar to that of Example I, using the appropriate reactants.

methyl carbamate) (8) l,l-diethylhydroxyguanidine O-(N-methyl carbamate) (9) I-ethyl-l-n-propylhydroxyguanidine methyl carbamate) (10) 1,1-di-n-propylhyd roxyguanidine O-(N-methyl carbamate) (1 l) 1,1-di-n-butylhydroxyguanidine O-(N-methyl carbamate) l2) hexahydro-N'-(methylcarbamoyloxy)- l H- azepine-l -carboxamidine (l3) l-methyll -benzylhydroxyguanidine methyl carbamate) (l4) l-methyll -cyclohexylhydroxyguanidine 0-( N- methyl carbamate) (l5) l-mcthyl-l-isopropylhydroxyguanidine O-(N- methyl carbamate) (l6) l-methyl-l-isobutylhydroxyguanidine ethyl carbamate) (l7) l-methyl-l-cyclopentylhydroxyguanidine O-(N- methyl carbamate) (l8) l,1-diallylhydroxyguanidine O-(N-methyl carbamate) (l9) l-methyl-l-(2,2-dimethoxyethyl)hdyroxyguanidine O-(N-methyl carbamate) (20) l,l-di(2-ethoxyethylhydroxyguanidine) 0-(N- methyl carbamate) (21) l-methyll -p-chlorobenzylhydroxyguanidine O-(N-methyl carbamate) (22) l-methyl-l-p-methoxybenzylhydroxyguanidine O-(N-methyl carbamate) (23) l-methyll -p-methylbenzylhydroxyguanidine O-(N-methyl carbamate) (24) l-methyl-l-p-nitrobenzylhydroxyguanidine 0- (N-methyl carbamate) (25) 1-methyl-l-(3,4-dichlorobenzylhydroxyguanidine) O-(N-methyl carbamate) (26) 1-methyl-l-(m-chlorobenzylhydroxyguanidine) O-(N-methyl carbamate) (27) l-ethyl-l-benzylhydroxyguanidine 0-(N-methyl carbamate) (28) l-n-propyl-l-benzylhydroxyguanidine methyl carbamate) (29) l-methyl-1-(B-phenethyl)hydroxyguanidine 0- (N-methyl carbamate) (30) l-methyl-l-p-fluorobenzylhydroxyguanidine 0 (Nmethyl. carbamate) (3]) l-ethyl-l-phcnylhydroxyguanidine 0-( N-methyl carbamate) (32) l-rrpropyl-l-phenylhydroxyguanidine methyl carbamate) EXAM PLE 3 3 l-Mcthyl-l-n-butylhydroxyguanidine O-Carbamate A solution of 4.05 g (0.05 mole) of potassium cyanate in l5 ml of water was added to a mixture of 7.25 g (0.05 mole) of l-methyl-l-n-butylhydroxyguanidine, 25 ml of water and 4.1 ml of concentrated hydrochloric acid. The mixture was stirred at room temperature for 4 days, then evaporated on a rotary evaporator. The residue was treated with 100 ml of acetonitrile and filtered to separate potassium chloride. The filtrate was evaporated and the residue chromatographed on 300 g of silica gel. Elution with chloroform gave 3.7 g of colorless oil (fractions 19-26, 250 ml each) that was identified as an :20 mixture of l-mcthyll -n-hutylhydroxyguanidine 0-carbamate and l-methyl-l-n-butylurea characterized by infrared and nuclear magnetic resonance spectroscopy.

nmr: 8 0.9 (t, 3); 1.4 (m, 4); 2.8 (s, 3); 3.l (t, 2); 4.7

(b, 2); 6.0 (b, 2). The impurity responsible for a singlet at 8 2.9 corresponds to about 20 percent of the above urea. Repetition of the chromatographic separation failed to remove the urea completely and an independent biological test showed that the urea was inactive as an antihypertensive agent.

TABLE l continued 9*3 C 11 CH3OCH-CH H CH2=CHCH CH =CHCH2- H n-Batyl BICH2CH2CH2- CH3 on cH3\- /H -CH CH CHQCHZ K CH CH 0CH CH -CI-l CH ClCH CH CH2CH -C H n-Propyl GH =CHCH C H n-Butyl CH2=CHCH CH C H EXAMPLE 37 The compounds of this invention are antihypertensive agents. They can be employed in pharmaceutical g ;g ;?;?gg methyl compositions composed of the active ingredient, i.e.,

lar way are shown in Table 5.

the compound(s) of the invention, in combination with physiologically inert pharmaceutical carriers and additives as is well known in the art. In the formulation of the antihypertensive composition, the active ingredient will ordinarily be present in an amount from about 0.5 to percent based on total weight of the composition.

Formulations include injectables and oral dosage forms such as tablets, hard and soft gelatin capsules, suspensions, syrups, elixirs and the like. Additives that can be employed in such formulations include solvents and diluents, lubricants, binding agents, disintegrants, preservatives, colorants, flavors and other additives which are common and well known to the art.

The compounds of this invention can be administered in the treatment of hypertension by any means that effects contact of the active ingredient with the site of action in the body of a warm-blooded animal. For example, administration can be parenterally, i.e., subcutaneously, intraveneously, intramuscularly or intraperitoneally. Alternatively or concurrently, administration can be by the oral route.

The dosage administered will be dependent upon the age, health and weight of the recipient. The extent of disease, kind of concurrent treatment, if any, frequency of treatment and the nature of the effect desired. Generally a daily dosage of active ingredient compound will be from about 0.01 to 50 milligrams per kilogram of body weight. Ordinarily from 0.05 to 40 and preferably 0.1 to 20 milligrams per kilogram per day in one or more applications per day is effective to obtain desired results. For more potent compounds of the invention the daily dosage ranges are from about 0.01 to 20 mg/kg, preferably 0.05 to 10 mg/kg, and more preferably 0.1 to 5 mg/kg.

The pharmaceutical carrier can be a sterile liquid such as water, or an oil, e.g., petroleum oil, animal oil, or vegetable oils such as peanul oil, soybean oil, mineral oil, sesame oil, and the like. In general, water, sa-

line, aqueous dextrose (glucose) and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are preferred liquid carriers, particularly for injectable solutions. Sterile injectable solutions will ordinarily contain from about 0.5 to 25 percent and preferably about 1 to percent by weight of the active ingredient.

Liquid oral administration can be in a suspension, syrup or elixir, in which the active ingredient ordinarily will constitute from about 0.5 to 10 percent and preferably about I to 5 percent by weight. The pharmaceutical carrier in such composition can be an aqueous vehicle such as an aromatic water, a syrup, a pharmaceutical mucilage, or a hydro-alcoholic elixir. Additional information concerning pharmaceutical carriers, diluents and additives can be found in the well-known reference test: Martin, Remingtons Pharmaceutical Sciences."

The following examples further illustrate the preparation of pharmaceutical compositions of the invention.

Example A A large number of unit capsules are prepared by filling standard two-piece hard gelatin capsules each with 50 mg of powdered active ingredient, 300 mg of lactose, 32 mg of talc and 8 mg of magnesium stearate.

Example B A mixture of the active ingredient in soybean oil is prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 35 mg of the active ingredient. The capsules are washed in petroleum ether and dried.

Example C A large number of tablets are prepared by conventional procedures so that the dosage unit is 75 mg of active ingredient, 7 mg of ethyl cellulose, 0.2 mg of colloidal silicon dioxide, 3 mg of magnesium stearate, l 1 mg of microcrystalline cellulose, l 1 mg of cornstarch and 98.8 g of lactose. Appropriate coatings may be applied to increase palatability or delay absorption.

Example D A parenteral composition suitable for administration Reduction 1n Blood l'renun 18 by injection is prepared by stirring 1.5 percent by weight of the active ingredient in 10 percent by volume propylene glycol and water. The solution is sterilized by filtration.

Example E An aqueous suspension is prepared for oral administration so that each 5 ml contain mg of finely divided active ingredient, 500 mg of acacia, 5 mg of sodium benzoate, 1.0 g of sorbitol solution, U.S.P., 5 mg of sodium saccharin and 0.025 ml of vanilla tincture.

The physical and biological properties of representative hydroxyguanidine O-carbamates are collected in Table 6.

The Table shows the antihypertensive activity of the compounds of the invention as evidenced by tests con ducted in hypertensive rats. In a test involving rats made hypertensive by repeated injections of desoxycorticosterone acetate (DOCA) according to the method described by Stanton and White [Arch. Intern. Pharmacodyn, 154, 351 (1965)], the compound of Example 1 is administered orally to each of eight or more test animals. The compound is prepared in an aqueous polyvinyl alcohol (PVA) acacia vehicle and administered at a volume to body weight ratio of 5.0 ml/kg. Systolic blood pressure is determined by the microphone-manometer technique [Friedman, M. and Freed, S. C., Pros. Soc. Exp. Biol. and Med., 70, 670 (1949)] at one or more time intervals afterdosing.

It is determined as a result of the test that 2.6 mg per kg (mg/kg) of the compound of Example I produces a 30 mm mercury (mm Hg) reduction in blood pressure compared with the blood pressure of a concurrently tested group of 16 or more rats that are orally dosed with only the aqueous PVA-acacia vehicle. Other compounds of the invention tested in a similar manner also show a significant activity in reducing blood pressure as is shown in Table 6.

It has also been determined that the compound of Example 4 significantly lowered the systolic and diastolic arterial blood pressure of anesthetized normotensive dogs when injected intravenously at cumulative doses of 2.7 mg/kg and above.

4 TABLE 6 Hydroxymenidine O-cn-bultel end their lhyaicnl and Antihyperteneive Properties m continua induction in biog: prawn-a m g R2 i In E E2 1 E I Anil- (Average) at 1 41 a. ew 101-2 cuac. 51.96 I 5.95 I 22.0 30 w a u n 1 8 LB? hur id c, 52.19; is, 6.0 iv, 22.21

ug emu, a; 6. broad, 1 6.84.1; n, a

u c 55.9 a 6.82 x 2 1 31 mm in -m menu so ms-11.5- a g: Pound e; 55.85, i, 6.65, 1, 2 1.

.7 2 a6 bran 2 6.6 brand, I. 7' o 5) z g-vrm M 111 89 Is-80' s o, t cum c, 57,59 2 3 :2 g I 0, H. :1 2535 2 .6 bros 2 6.5 broad, 1 7.3 m,

gnu-um 1. m 4.... .JL. A". 112.5221: 5 a ML 2 10.0 on o. b 1.14 r: 33 a '9 I 7 2.8 a) 5 3.1 it) i 0 .35 I 5 5 8 -35: I -21 mm if; $1,233; g MM 5:38: a: 6.13; mi ems 1 5) 2x 1: R

' 1 1 1 1 1 a1 rib-115' o 1.2 a. 12); 2.9 (a, 3); cne'a c, :9. 8; a 9.52: I. 25-90 mm mm I 15 f a m, mm: c, 0.;2; K: 9-. 26-18 2); 6.6 (broad, 1)

s m1 mum new: 36 131-2 syn/anti lixtuu mm c, 11.51; a, 8.97: x. 21.70 Found C, 7.10; H, 8.9%; II, 27-55 1,; 1 bn1mm induction in am .11. 1 4L m 329. 5.. *-r M 3'! uei l my: pbonyl new; 61 1! 90-21400) 0 2.7 (l. 6); 2.9 Oiled c. 55.92: H. 633: I. 23.71 (d, 3); 6.3-7.1; Pound c, 55.61; a, 6.71; n, 2332 The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

l. A compound of the formula 0 l N-O-C-NHR n n-c-mm wherein X is F, Cl, C -C alkyl, C -C alkoxy, N0 CP R R NCO, R R NSO or R m O2 n 0-3 R and R are H or C C. alkyl; R is CF or C -C alkyl; R is hydrogen or C -C alkyl; and with the proviss that 1. up to one of R, R and R is selected from (A) up to two of R, R and R is selected from (B), and up to one of R, R and R is selected from (C); 2. when R is methyl and R is hydrogen, R is not unsubstituted phenyl or unsubstituted benzyl; 3. when R is methyl and R is hydrogen. R is not unsubstituted phenyl; and 4. when one of R, R and R is hydrogen and the other two R groups are selected from (B), the total carbon atoms in the said other two groups is 3-9. 2. A compound according to claim 1 wherein one of R and R is selected from (B), the other is selected from (C), and R is hydrogen.

3. A compound according to claim 1 wherein R and R are each selected from (B) and R is hydrogen.

4. A compound according to claim I wherein R or R is selected from (B). the other of R or R is hydrogen and R is selected from (B).

9. A compound according to claim 1 which is l-ethyll-phcnylhydroxyguanidine O-(N-mcthyl carbamate).

10. A compound according to claim 1 which is l-npropyl-l-phcnylhydroxyguanidine O-(N-methyl carbamate).

11. A compound according to claim 1 which is 1,1- di-n-propylhydroxyguanidine O-(N-methyl carbamate).

12. A compound according to claim 1 which is lmethyl-l-benzylhydroxyguanidine O-(N-methyl carbamate). 

1. UP TO ONE OF R1, R2 AND R3 IS SELECTED FROM (A) UP TO TWO OF R1, R2 AND R3 IS SELECTED FROM (B), AND UP TO ONE IF R1, R2 AND R3 IS SELECTED FROM (C),
 1. A COMPOUND OF THE FORMULA
 2. WHEN R1, IS METHYL AND R2 IS HYDROGEN, R3 IS NOT UNSUBSTITUTED PHENYL OR UNSUBSTITUTED BENZYL,
 2. when R1 is methyl and R2 is hydrogen, R3 is not unsubstituted phenyl or unsubstituted benzyl;
 2. A compound according to claim 1 wherein one of R1 and R2 is selected from (B), the other is selected from (C), and R3 is hydrogen.
 3. when R1 is methyl and R3 is hydrogen, R2 is not unsubstituted phenyl; and
 3. A compound according to claim 1 wherein R1 and R2 are each selected from (B) and R3 is hydrogen.
 3. WHEN R1 IS METHYL AND R3 IS HYDROGEN, R2 IS NOT UNSUBSTITUTED PHENYL, AND
 4. WHEN ONE OF R1, R2 AND R3 IS HYDROGEN AND THE OTHER TWO R GROUPS ARE SELECTED FROM (B), THE TOTAL CARBON ATOMS IN THE SAID OTHER TWO GROUPS IS 3-9.
 4. A compound according to claim 1 wherein R1 or R2 is selected from (B), the other of R1 or R2 is hydrogen and R3 is selected from (B).
 4. when one of R1, R2 and R3 is hydrogen and the other two R groups are selected from (B), the total carbon atoms in the said other two groups is 3-9.
 5. A compound according to claim 1 which is 1-methyl-1-p-fluorobenzylhydroxyguanidine 0-(N-methyl carbamate).
 6. A compound according to claim 1 which is 1-methyl-1-p-chlorobenzylhydroxyguanidine 0-(N-methyl carbamate).
 7. A compound according to claim 1 which is 1-methyl-1-p-nitrobenzylhydroxyguanidine 0-(N-methyl carbamate).
 8. A compound according to claim 1 which is 1-methyl-1-i-butylhydroxyguanidine 0-(N-methyl carbamate).
 9. A compound according to claim 1 which is 1-ethyl-1-phenylhydroxyguanidine 0-(N-methyl carbamate).
 10. A compound according to claim 1 which is 1-n-propyl-1-phenylhydroxyguanidine 0-(N-methyl carbamate).
 11. A compound according to claim 1 which is 1,1-di-n-propylhydroxyguanidine 0-(N-methyl carbamate).
 12. A compound according to claim 1 which is 1-methyl-1-benzylhydroxyguanidine 0-(N-methyl carbamate). 